[go: up one dir, main page]
More Web Proxy on the site http://driver.im/

EP1682061B1 - Dispositif d'administration de medicaments par voie transdermique - Google Patents

Dispositif d'administration de medicaments par voie transdermique Download PDF

Info

Publication number
EP1682061B1
EP1682061B1 EP04810038.2A EP04810038A EP1682061B1 EP 1682061 B1 EP1682061 B1 EP 1682061B1 EP 04810038 A EP04810038 A EP 04810038A EP 1682061 B1 EP1682061 B1 EP 1682061B1
Authority
EP
European Patent Office
Prior art keywords
acrylic
drug delivery
based polymer
transdermal drug
use according
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
EP04810038.2A
Other languages
German (de)
English (en)
Other versions
EP1682061A4 (fr
EP1682061A2 (fr
Inventor
David P. Kanios
Rod Hartwig
Juan A. Mantelle
David W. Houze
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Noven Pharmaceuticals Inc
Original Assignee
Noven Pharmaceuticals Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Noven Pharmaceuticals Inc filed Critical Noven Pharmaceuticals Inc
Publication of EP1682061A2 publication Critical patent/EP1682061A2/fr
Publication of EP1682061A4 publication Critical patent/EP1682061A4/fr
Application granted granted Critical
Publication of EP1682061B1 publication Critical patent/EP1682061B1/fr
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F13/00—Bandages or dressings; Absorbent pads
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
    • A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
    • A61K9/7038—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
    • A61K9/7046—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds
    • A61K9/7053—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds obtained by reactions only involving carbon to carbon unsaturated bonds, e.g. polyvinyl, polyisobutylene, polystyrene
    • A61K9/7061—Polyacrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
    • A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
    • A61K9/7084—Transdermal patches having a drug layer or reservoir, and one or more separate drug-free skin-adhesive layers, e.g. between drug reservoir and skin, or surrounding the drug reservoir; Liquid-filled reservoir patches
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F13/00—Bandages or dressings; Absorbent pads
    • A61F13/02—Adhesive bandages or dressings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A61K31/566—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol having an oxo group in position 17, e.g. estrone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A61K31/567—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in position 17 alpha, e.g. mestranol, norethandrolone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
    • A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
    • A61K9/7038—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
    • A61K9/7046—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds
    • A61K9/7069—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds obtained otherwise than by reactions only involving carbon to carbon unsaturated bonds, e.g. polysiloxane, polyesters, polyurethane, polyethylene oxide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
    • A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
    • A61K9/7092—Transdermal patches having multiple drug layers or reservoirs, e.g. for obtaining a specific release pattern, or for combining different drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • A61P5/30—Oestrogens

Definitions

  • This invention relates generally to transdermal drug delivery systems, and more particularly to pharmaceutically acceptable adhesive matrix compositions.
  • the invention additionally relates to transdermal drug delivery systems where the drug permeation, delivery rates and profiles can be selectively modulated within the transdermal drug delivery system.
  • the present invention relates to transdermal delivery systems, their method of making and method of use.
  • the present invention is directed to a transdermal drug delivery system for use in the treatment of Attention Deficit Disorder or for use in appetite suppression, said composition comprising a backing layer; at least one adhesive coating layer comprising at least one acrylic-based polymer, a first surface of said at least one adhesive coating layer being affixed to one surface of said backing layer; at least one carrier composition layer comprising at least one acrylic-based polymer, a first surface of said at least one carrier composition layer being affixed to a second surface of said at least one adhesive coating layer; and a removable release liner affixed to a second surface of said at least one carrier composition layer, wherein said at least one carrier composition layer includes a therapeutically effective amount of d-amphetamine base or of d-amphetamine base and I-amphetamine base incorporated into the at least one carrier composition layer, and wherein the coat weight, monomeric makeup, and/or functionality of said adhesive coating layer are
  • the adhesive coated backing or release liner is processed or manufactured separately from the polymeric and/or adhesive drug carrier layers to prevent or minimize loss of drug or other system components, and combined prior to topical application.
  • the drug delivery rate and profile can be further controlled by adjusting certain characteristics of the polymers and/or adhesives themselves or of the method of making the system, relative to the active agent's properties in this transdermal system.
  • transdermal drug delivery system as a means for administering therapeutically effective amounts of an active agent is well known in the art.
  • Transdermal devices or systems can be categorized in many different ways, but those commonly called transdermal patches, incorporate the active agent into a carrier, usually a polymeric and/or a pressure-sensitive adhesive formulation.
  • the simplest in design is one in which the drug is incorporated into a pressure-sensitive adhesive carrier layer, each surface of which is affixed to a polymeric film/layer -- one serving as the backing (to anchor the carrier layer and control passage of environmental influences in and system components out during use) and the other serving as a removable liner (to protect the carrier layer prior to use but removed upon topical application of the carrier layer).
  • a pressure-sensitive adhesive carrier layer each surface of which is affixed to a polymeric film/layer -- one serving as the backing (to anchor the carrier layer and control passage of environmental influences in and system components out during use) and the other serving as a removable liner (to protect the carrier layer prior to use but removed upon topical application of the carrier layer).
  • a drug's delivery rate is affected by its degree of saturation and solubility in the carrier composition.
  • the amount of drug needed to be incorporated into a single, adhesive carrier or matrix composition i.e., drug loading
  • Drug carrier compositions typically require one or more processing solvents, usually organic solvents, in which to incorporate the active agent and/or allow the polymeric/adhesive carrier to be more easily coated onto a backing or release liner. Removal of such solvents is necessary for avoiding problems associated with residual solvent amounts, such as irritation at the topical site of application, drug degradation, drug instability, loss of adhesive or cohesive properties impacting attachment of the system to the user and loss of desired delivery amount or rate. Solvent removal requires that elevated temperatures be applied to the carrier composition to evaporate such solvents. But at the same time, removal of solvents by use of elevated temperatures can also remove or evaporate other desirable components, such as the active agent and drug permeation enhancers. Their loss can even occur at temperatures below which such components may otherwise volatilize by virtue of their interaction with each other and with the other carrier components (relative volalitility or reactivity).
  • processing solvents usually organic solvents
  • Formulating with low molecular weight drugs that are liquid at or near room temperatures is further particularly difficult in adhesive carrier layer compositions because such drugs more readily or easily permeate skin or mucosa.
  • Such systems often cannot be adequately optimized to control onset of delivery (i.e., slow down or retard) and/or maintain delivery for an extended duration of delivery without compromising other design and performance factors and considerations.
  • US 2003/0170195 A discloses a dermal composition comprising a combination of acrylic-based polymers, and e.g. d-amphetamine.
  • a particularly preferred low molecular weight drug that is liquid at or near room temperatures
  • the drug is volatile at room temperature.
  • the drug degrades in the presence of certain solvents, particularly ethyl acetate.
  • the drug degrades into the carbonate form in the presence of carbon dioxide commonly found in atmospheric air. Accordingly, manufacturing a transdermal system using processing solvents and effectively deliver such a drug is even more problematic.
  • transdermal carrier compositions based on acrylic pressure-sensitive adhesive polymers are often preferred for their ability to incorporate or solubilize many drugs.
  • acrylic-based pressure-sensitive adhesives are typically polymerized with functional monomers to provide functional groups on the acrylic-based adhesive.
  • a problem associated with the use of such acrylic-based polymers with functional groups is that due to the generally high solubility of the drug, a large amount of drug generally must be incorporated into the composition to saturate it and provide an adequate drug release to the skin of the user. In use with low molecular weight drugs or controlled substances, the loss of the drug in the manufacturing process again can be a significant problem.
  • rate controlling membranes and/or multiple layers have been made to utilize rate controlling membranes and/or multiple layers, and to dissolve or suspend certain drugs in thermoplastic type carrier compositions without the use of solvents.
  • These drug delivery devices generally do not allow a great amount of flexibility in effectively controlling the release rate of a variety of drugs, which in turn also severely limits their therapeutic application, and are expensive or burdensome to manufacture.
  • multiple adhesive layers are often required to affix the other layers or membranes to each other, and/or to the site of topical application.
  • the present invention provides a transdermal drug delivery system for use in the treatment of Attention Deficit Disorder or for use in appetite suppression, said composition comprising a backing layer; at least one adhesive coating layer comprising at least one acrylic-based polymer, a first surface of said at least one adhesive coating layer being affixed to one surface of said backing layer; at least one carrier composition layer comprising at least one acrylic-based polymer, a first surface of said at least one carrier composition layer being affixed to a second surface of said at least one adhesive coating layer; and a removable release liner affixed to a second surface of said at least one carrier composition layer, wherein said at least one carrier composition layer includes a therapeutically effective amount of d-amphetamine base or of d-amphetamine base and I-amphetamine base incorporated into the at least one carrier composition layer, and wherein the coat weight, monomeric
  • the backing composite comprising a non-drug containing adhesive coating, which may contain low boiling point or volatile components such as permeation enhancers, is affixed or applied to the drug-impermeable layer.
  • the active agent carrier layer comprising a pressure-sensitive adhesive composition and the drug incorporated therein is affixed to the backing composite.
  • the polymeric coating is designed to provide control of permeation rate, onset and profile of the active agent from the system.
  • the agent-carrier composition may comprise one or more layers.
  • the agent-carrier composition may comprise at least one layer formed of a blend of at least one acrylic-based polymer and at least one silicone-based polymer, to serve as a pressure-sensitive adhesive composition for applying the system to the dermis, or a blend of acrylic-based polymers.
  • the non-drug containing acrylic-based coating designed to interact with the drug composition layer(s).
  • the invention is also directed to methods of manufacturing a transdermal delivery system as defined in claims 39 and 41.
  • the delivery rate, onset of delivery (lag time) and delivery profile of the drug may be selectively modulated by one or more of (a) increasing or decreasing the thickness or coat weight of the acrylic-based adhesive coating per cm 2 as applied to the backing of the system, (b) manipulating the moiety or functionality of the acrylic-based adhesive coating, and (c) manipulating the monomeric composition and/or ratios of the acrylic-based adhesive coating.
  • Either the non-drug containing coating or the carrier composition must also be a pressure-sensitive adhesive when used as area of attachment to the skin or mucosa of the user.
  • the drug carrier composition may be comprised of (a) one or more acrylic-based polymers having one or more functionality alone or in combination with (b) one or more silicone-based polymers having one or more silanol contents (capping) and/or resin to polymer ratios, and are present in proportions to provide a desired solubility for the drug. Further manipulation of drug delivery, onset and profiles can be achieved by varying the concentrations of the drug in the drug-loaded carrier.
  • mucosa as used herein means any moist anatomical membrane or surface on a mammal such as oral, buccal, vaginal, rectal, nasal or ophthalmic surfaces.
  • skin is meant to include mucosa, which further includes oral, buccal, nasal, rectal and vaginal mucosa.
  • transdermal refers to delivery, administration or application of a drug by means of direct contact with tissue, such as skin or mucosa. Such delivery, administration or application is also known as percutaneous, dermal, transmucosal and buccal.
  • blend and “mixture” are used herein to mean that there is no, or substantially no, chemical reaction or crosslinking (other than simple H-bonding) between the different polymers in the polymer matrix.
  • crosslinking between a single polymer component is fully contemplated to be within the scope of the present invention.
  • the term "adhesive” means a substance, inorganic or organic, natural or synthetic that is capable of surface attachment at the intended topical application site by itself or functions as an adhesive by admixture with tackifiers, plasticizers, cross-linking agents or other additives.
  • the carrier of the present invention is a "pressure-sensitive adhesive” which refers to a viscoelastic material which adheres instantaneously to most substrates with the application of very slight pressure and remains permanently tacky.
  • a polymer or dermal composition is a pressure-sensitive adhesive within the meaning of the term as used herein if it has the adhesive properties of a pressure-sensitive adhesive per se or functions as a pressure-sensitive adhesive by admixture with tackifiers, plasticizers, cross-linking agents or other additives.
  • a "polymer composition of two or more polymers” is defined as a physical blend of at least two polymers and can include 3 or more polymers.
  • the two or more polymers may include the acrylic-based polymers described herein and can optionally include other polymers discussed more fully below.
  • the term "acrylic-based" polymer is defined as any polyacrylate, polyacrylic, acrylate and acrylic polymer.
  • the acrylic-based polymers can be any of the homopolymers, copolymers, terpolymers, and the like of various acrylic acids or esters.
  • the acrylic-based polymers useful in practicing the invention are polymers of one or more monomers of acrylic acids and other copolymerizable monomers.
  • the acrylic-based polymers also include copolymers of alkyl acrylates and/or methacrylates and/or copolymerizable secondary monomers. Acrylic-based polymers with functional groups as described more fully below, are copolymerized with functional monomers.
  • ком ⁇ онент is broadly defined as a measure of the type and quantity of functional groups that a particular acrylic-based polymer has. This definition also encompasses acrylic-based polymers having no or substantially no functional groups.
  • ком ⁇ онентs or groups are monomer units in acrylic-based polymers which have reactive chemical groups which modify the acrylic-based polymers directly or provide sites for further reactions.
  • functional groups include carboxyl, epoxy and hydroxy groups.
  • non-functional acrylic-based polymer is defined as an acrylic-based polymer that has no or substantially no functional reactive moieties present in the acrylic. These are generally acrylic esters which can be copolymerized with other monomers which do not have functional groups, such as vinyl acetate.
  • carrier refers to any non-aqueous material known in the art as suitable for transdermal drug delivery administration, and includes any polymeric material into which an active agent may be solubilized in combination or admixture with the other ingredients of the composition.
  • the polymeric materials preferably comprise adhesives and, in particular, pressure-sensitive adhesives.
  • the carrier material is typically used in an amount of about 40% to about 90%, and preferably from about 50% to about 80%, by weight based on the dry weight of the total carrier composition.
  • carrier composition may also refer to enhancers, solvents, co-solvents and other types of addictives useful for facilitating transdermal drug delivery.
  • the carrier compositions of the present invention can also contain one or more non-aqueous solvents and/or co-solvents.
  • solvents and/or co-solvents are those known in the art, and are non- toxic, pharmaceutically acceptable substances, preferably non-aqueous liquids, which do not substantially negatively affect the adhesive properties or the solubility of the active agents at the concentrations used.
  • the solvent and/or co-solvent can be for the active agent or for the carrier materials, or both.
  • Suitable solvents include volatile processing liquids such as alcohols (e.g., methyl, ethyl, isopropyl alcohols and methylene chloride); ketones (e.g., acetone); aromatic hydrocarbons such as benzene derivatives (e.g., xylenes and toluenes); lower molecular weight alkanes and cycloalkanes (e.g., hexanes, heptanes and cyclohexanes); and alkanoic acid esters (e.g., ethyl acetate, n-propyl acetate, isobutyl acetate, n-butyl acetate isobutyl isobutyrate, hexyl acetate, 2-ethylhexyl acetate or butyl acetate); and combinations and mixtures thereof.
  • alcohols e.g., methyl, ethyl, isopropyl alcohols and
  • suitable co-solvents include polyhydric alcohols, which include glycols, triols and polyols such as ethylene glycol, diethylene glycol, propylene glycol, dipropylene glycol, trimethylene glycol, butylene glycol, polyethylene glycol, hexylene glycol, polyoxethylene, glycerin, trimethylpropane, sorbitol, polyvinylpyrrolidone, and the like.
  • polyhydric alcohols include glycols, triols and polyols such as ethylene glycol, diethylene glycol, propylene glycol, dipropylene glycol, trimethylene glycol, butylene glycol, polyethylene glycol, hexylene glycol, polyoxethylene, glycerin, trimethylpropane, sorbitol, polyvinylpyrrolidone, and the like.
  • co-solvents may include glycol ethers such as ethylene glycol monoethyl ether, glycol esters, glycol ether esters such as ethylene glycol monoethyl ether acetate and ethylene glycol diacetate; saturated and unsaturated fatty acids, mineral oil, silicone fluid, lecithin, retinol derivatives and the like, and ethers, esters and alcohols of fatty acids.
  • glycol ethers such as ethylene glycol monoethyl ether, glycol esters, glycol ether esters such as ethylene glycol monoethyl ether acetate and ethylene glycol diacetate
  • saturated and unsaturated fatty acids mineral oil, silicone fluid, lecithin, retinol derivatives and the like, and ethers, esters and alcohols of fatty acids.
  • the solvents or co-solvents used in accordance with the invention are desirably a low volatile solvent that does not require excessive temperatures for evaporation thereof.
  • the term "solubilized” is intended to mean that in the carrier composition there is an intimate dispersion or dissolution of the active agent at the crystalline, molecular or ionic level, such that crystals of the active agent cannot be detected using a microscope having a magnification of 25X. As such, the active agent is considered herein to be in "non-crystallized” form when in the compositions of the present invention.
  • therapeutically effective means an amount of an active agent that is sufficient to achieve the desired local or systemic effect or result, such as to prevent, cure, diagnose, mitigate or treat a disease or condition, when applied topically over the duration of intended use.
  • the amounts necessary are known in the literature or may be determined by methods known in the art, but typically range from about 0.1 mg to about 20,000 mg, and preferably from about 0.1 mg to about 1,000 mg, and most preferably from about 0.1 to about 500 mg per human adult or mammal of about 75 kg body weight per 24 hours.
  • the term "user” or “subject” is intended to include all warm-blooded mammals, preferably humans.
  • transdermal drug delivery system 10 comprises a carrier composition layer 12 incorporating the active agent.
  • Surface 14 of the adhesive carrier layer 12 is affixed to release liner 15 to protect the carrier layer prior to use but which is removed upon topical application of the carrier layer to the skin or mucosa of the user.
  • a non-drug containing polymeric and/or adhesive coating 18 is affixed to backing 20 on one surface, with the other surface being affixed to carrier layer 12.
  • Backing composite 16 comprises coating 18 affixed to backing 20, which as described later, is made or processed separately from carrier layer 12 affixed to release liner 15.
  • Carrier composition layer 12 can comprise any polymer or adhesive generally known in the art for formulating a drug carrier composition, and include all of the non-toxic natural and synthetic polymers known or suitable for use in transdermal systems including solvent-based, hot melt and grafted adhesives, and may be used alone or in combinations, mixtures or blends. Examples include acrylic-based, silicone-based, rubbers, gums, polyisobutylenes, polyvinylethers, polyurethanes, styrene block copolymers, styrene/butadiene polymers, polyether block amide copolymers, ethylene/vinyl acetate copolymers, and vinyl acetate based adhesives, and bioadhesives set forth in U.S. Pat. No. 6,562,363 .
  • silicone-based polymer is intended to be used interchangeably with the terms siloxane, polysiloxane, and silicones as used herein and as known in the art.
  • the silicone-based polymer may also be a pressure-sensitive adhesive, with a polysiloxane adhesive prepared by cross-linking an elastomer, typically a high molecular weight polydiorganosiloxane, with a resin, to produce a three-dimensional siloxane structure, via a condensation reaction in an appropriate organic solvent.
  • the ratio of resin to elastomer is a critical factor that can be adjusted in order to modify the physical properties of polysiloxane adhesives.
  • Suitable silicone pressure-sensitive adhesives are commercially available and include the silicone adhesives sold under the trademarks BIO-PSA® by Dow Corning Corporation, Medical Products, Midland, Michigan (such as -2685, -3027, - 3122, -4101, -4102, -4203, -4301, -4302, -4303, -4401 -4403, -4501, -4503, -4602, - 4603 and -4919). Capped silicones with high resin content are preferred.
  • the acrylic-based polymer can be any of the homopolymers, copolymers, terpolymers, and the like of various acrylic acids.
  • the acrylic-based polymer constitutes from about 2% to about 95% of the total dry weight of the of the carrier composition, and preferably from about 2% to about 90%, and more preferably from about 2% to about 85%, wherein the amount of the acrylic-based polymer is dependent on the amount and type of drug used.
  • the acrylic-based polymers usable in the invention are polymers of one or more monomers of acrylic acids and other copolymerizable monomers.
  • the acrylate polymers also include copolymers of alkyl acrylates and/or methacrylates and/or copolymerizable secondary monomers or monomers with functional groups. By varying the amount of each type of monomer added, the cohesive properties of the resulting acrylate polymer can be changed as is known in the art.
  • the acrylate polymer is composed of at least 50% by weight of an acrylate or alkyl acrylate monomer, from 0 to 20% of a functional monomer copolymerizable with the acrylate, and from 0 to 40% of other monomers.
  • Acrylate monomers which can be used include acrylic acid, methacrylic acid, butyl acrylate, butyl methacrylate, hexyl acrylate, hexyl methacrylate, 2-ethylbutyl acrylate, 2-ethylbutyl methacrylate, isooctyl acrylate, isooctyl methacrylate, 2-ethylhexyl acrylate, 2-ethylhexyl methacrylate, decyl acrylate, decyl methacrylate, dodecyl acrylate, dodecyl methacrylate, tridecyl acrylate, and tridecyl methacrylate.
  • Functional monomers, copolymerizable with the above alkyl acrylates or methacrylates which can be used include acrylic acid, methacrylic acid, maleic acid, maleic anhydride, hydroxyethyl acrylate, hydroxypropyl acrylate, acrylamide, dimethylacrylamide, acrylonitrile, dimethylaminoethyl acrylate, dimethylaminoethyl methacrylate, tert-butylaminoethyl acrylate, tert-butylaminoethyl methacrylate, methoxyethyl acrylate and methoxyethyl methacrylate.
  • Suitable acrylic-based polymers may also be a pressure-sensitive adhesive which are commercially available and include the acrylic-based adhesives sold under the trademarks Duro-Tak® by National Starch and Chemical Corporation, Bridgewater, N.J. (such as 87-2287, -4098, -2852, -2196, -2296, -2194, -2516, -2070, -2353, - 2154, -2510, -9085 and -9088).
  • Other suitable acrylic-based adhesives include HRJ 4483, 10127, and 11588 sold by Schenectady International, Inc., Schenectady, N.Y., and those sold by Monsanto; St. Louis, Mo., under the trademarks Gelva® Multipolymer Solution (such as 2480, 788, 737, 263, 1430, 1753, 1151, 2450, 2495, 3067, 3071, 3087 and 3235.
  • the carrier composition may comprise blends of acrylic-based polymers, silicone-based polymers and rubbers based upon their differing solubility parameters, alone or in combination with other polymers, for example polyvinylpyrrolidone, as more fully described in U.S. Pat. Nos.: 5,474,783 ; 5,656,286 ; 5,958,446 ; 6,024,976 ; 6,221,383 ; and 6,235,306 .
  • the amount of each polymer is selected to adjust the saturation concentration of the drug in the multiple polymer system, and to result in the desired rate of delivery of the drug from the system and through the skin or mucosa.
  • Acrylic-based polymers having functional groups are copolymers or terpolymers which contain in addition to nonfunctional monomer units, further monomer units having free functional groups.
  • the monomers can be monofunctional or polyfunctional. These functional groups include carboxyl groups, hydroxy groups, amino groups, amido groups, epoxy groups, etc. Preferred functional groups are carboxyl groups and hydroxy groups.
  • Preferred carboxyl functional monomers include acrylic acid, methacrylic acid, itaconic acid, maleic acid, and crotonic acid.
  • Preferred hydroxy functional monomers include 2-hydroxyethyl methacrylate, 2-hydroxyethyl acrylate, hydroxymethyl acrylate, hydroxymethyl methacrylate, hydroxyethyl acrylate, hydroxyethyl methacrylate, hydroxypropyl acrylate, hydroxypropyl methacrylate, hydroxybutyl acrylate, hydroxybutyl methacrylate, hydroxyamyl acrylate, hydroxyamyl methacrylate, hydroxyhexyl acrylate, hydroxyhexyl methacrylate.
  • Non-functional acrylic-based polymers can include any acrylic based polymer having no or substantially no free functional groups.
  • the acrylic based polymer can include homopolymers, copolymers and terpolymers.
  • the monomers used to produce the polymers can include alkyl acrylic or methacrylic esters such as methyl acrylate, ethyl acrylate, propyl acrylate, amyl acrylate, butyl acrylate, 2-ethylbutyl acrylate, hexyl acrylate, heptyl acrylate, octyl acrylate, nonyl acrylate, 2-ethylhexyl acrylate, decyl acrylate, dodecyl acrylate, tridecyl acrylate, glycidyl acrylate and the corresponding methacrylic esters.
  • alkyl acrylic or methacrylic esters such as methyl acrylate, ethyl acrylate, propyl acrylate, amyl acrylate, butyl acrylate, 2-ethylbutyl acrylate, hexyl acrylate, heptyl acrylate, octyl
  • Both the acrylic-based polymer having substantially no functional groups and acrylic-based polymers having functional groups can optionally include further modifying monomers.
  • These modifying monomers can include any conceivable monomer that is capable of undergoing vinyl polymerization.
  • the incorporation of styrene monomers can be used to increase the glass transition temperature and are sometimes used to improve the cohesive strength.
  • the copolymerization of vinyl acetate monomers with acrylic esters are also used to form acrylic-based polymers.
  • Ethylene can also be copolymerized with acrylic esters and vinyl acetate to give suitable acrylic-based polymers.
  • a composition will require less of a functional acrylic that contains 20% by weight of functional groups as opposed to one that contains 0.5% by weight of functional groups to achieve the same effect required for solubility and flux.
  • the amount of functional acrylic is generally within the range of about 1 to 99 weight % and preferably 5 to 95 weight %, more preferably 20 to 75 weight %, even more preferably 30 to 65 weight %, based on the total polymer content of the transdermal composition.
  • the amount of non-functional acrylic or acrylic with a functional group which does not have as great of an affinity for the drug is within the range of about 99 to 1 weight %, preferably 95 to 5 weight %, more preferably 75 to 20 weight % and even more preferably 30 to 65 weight %, based on the total polymer content of the composition.
  • the required proportions of acrylic-based or other polymers used are generally dependant on the specific drug, its desired delivery rate and the desired duration of drug delivery. In general, proportions of acrylic-based polymers also depend on the content of the functional monomer units in the functional acrylic.
  • the drug carrier composition When the drug carrier composition is intended to function as the face layer, that is the layer that comes in contact with the topical site of application as depicted in Fig. 1 , it is preferable that the carrier composition comprise a pressure-sensitive adhesive or bioadhesive.
  • the drug carrier composition is designed to minimize or prevent the loss of drug and/or other desirable volatile components, such as hydrophillic permeation enhancers, in compositions containing processing solvents, as well as provide selectable modulation of delivery rates, onset and profiles of the drug when used in combination with a non-drug containing polymeric and/or adhesive coating that is applied to either the transdermal system's backing or release liner.
  • desirable volatile components such as hydrophillic permeation enhancers
  • Minimizing or preventing drug loss is particularly desirable when trying to deliver controlled substances.
  • drugs that have relatively low boiling or melting points such as drugs that are liquid at or near room temperature, or are easily volatilized and/or degraded during the manufacture of the transdemal delivery system one can experience drug loss during processing. This is particularly relevant for controlled substances for which regulatory agencies, such as the FDA, require accountability for any loss of the controlled substance.
  • Particular drugs that are usable in the present invention include low molecular weight drugs. Any drug which is liquid at or about room temperature can be used according to the present invention.
  • the term "low molecular weight" is defined to include any drug and its equivalent forms that has a melting point such that it exists as a liquid at or about room temperatures.
  • This term encompasses low molecular weight drugs having a molecular weight of less than about 300 daltons.
  • a drug which is of low molecular weight and liquid at or about room temperatures is generally in its free-base or free-acid form, and, as such, is encompassed by this term.
  • Drugs usable in practicing the invention include amphetamine, d-amphetamine, methaphetame, prilocaine, benzocaine, butacaine, butamben, butanilicaine, corticaine, lidocaine, memantine, pilocarpine,cyclobenzaprine, paroxetine, fluoxetine, duloxetine, imipramine, decipramine, doxeprin, nortriptylene, protriptylene, bupropion, azelastine, chlorphenamine, bisoprolol, pheniramine, alprazolam, captopril, clonidine, clonazepam, enalapril, ramipril, haloperidol, ketoprofen, loratadine, methimazole (anti-hyperthyroid), methylphenidate, methyl testosterone, nicotine, nitroglycerin, pramipexole, ropinirole, hydromorphone, selegiline (
  • transdermal delivery of d-amphetamine base or of a combination of d-amphetamine base and 1-amphetamine base is used to treat Attention Deficit and Hyperactivity disorders, and appetite suppression.
  • Transdermal delivery of a combination of d-amphetamine base and 1-amphetamine base is preferably used to treat Attention Deficit and Hyperactivity disorders, and appetite suppression wherein the d to 1 ratio of the amphetamine base is between about 1 to 1 to about 4 to 1.
  • Transdermal delivery of a combination of d-amphetamine base and 1-amphetamine base is preferably used to treat Attention Deficit and Hyperactivity disorders, and appetite suppression wherein the d to 1 ratio of the amphetamine base is between about 3 to 1 to about 4 to 1.
  • any molecular weight drug and its equivalent forms can be used in the present invention as long as such drugs would be substantially unstable or be substantially evaporated or driven-off at the temperatures generally known or used in the art to remove solvents during the manufacturing processing, typically in the range of 71.1°C to 121°C (160°F to 250°F), by their own properties or by virtue of their relative volatility or reactivity with the other carrier components.
  • the preferred drug is one that is hydrophillic and not relatively volatile or reactive with the other carrier components, but which is incorporated into a carrier composition with certain co-solvents or enhancers preferred for use with such drugs that would be, by their own properties or by virtue of their relative volatility or reactivity with the other carrier components, substantially unstable or substantially evaporated or driven-off at the temperatures generally known or used in the art to remove solvents during the manufacturing processing.
  • the drugs and mixtures thereof can be present in the composition in different forms, depending on which yields the optimum delivery characteristics.
  • the drug can be in its free base form or in the form of salts, esters, or any other pharmacologically acceptable derivatives, or as prodrugs, components of molecular complexes or as combinations of these.
  • Any drug suitable for transdermal administration by methods previously known in the art and by the methods of the present invention can be used in the present invention, and further include such active agents that may be later established as drugs and are suitable for delivery by the present invention.
  • These drugs include but are not limited to those categories and species of drugs set forth on page ther-1 to ther-28 of the Merck Index, 12th Edition Merck and Co. Rahway, N.J. (1999 ).
  • Exemplary of drugs that can be administered by the novel dermal drug delivery system include, but are not limited to:
  • the amount of drug and the rate of release is typically selected so as to provide delivery characterized by a pseudo-zero order time dependency for a prolonged period of time.
  • the minimum amount of drug in the system is selected based on the amount of drug which passes through the skin or mucosa in the time span for which the device is to provide a therapeutically effective amount.
  • the amount of drug in the transdermal system can vary from about 0.1 to 40% by weight, preferably 0.5 to 30% by weight, and optimally 1-20% weight per cent, based on the total dry weight of the agent-carrier composition.
  • the inventors have found that by preparing and processing the drug carrier composition and polymeric coating separately, greater flexibility is afforded when manufacturing a transdermal device employing processing solvents or solvent-based adhesives.
  • solvents are typically volatile, non-aqueous liquids, and are used to solubilize or dissolve the active agent and polymers together into a composition that can more easily be processed into a transdermal system, such as by coating or casting.
  • Typical liquids are volatile polar and non-polar organic liquids such as lower molecular weight alkanols (e.g., isopropanol and ethanol), aromatics such as benzene derivatives (e.g., xylene and toluene), lower molecular weight alkanes and cycloalkanes (e.g., hexane, heptane and cyclohexane) and alkanoic acid esters such as ethyl or butyl acetate.
  • Such solvents are sometimes added to the carrier composition (also referred to as co-solvents) and are typically found in the commercially available adhesives as is known in the art to prepare transdermal systems.
  • the drug carrier composition should be substantially free of residual solvents after manufacture, preferably less than 0.5% and more preferably 0.2% or less.
  • the amount of processing solvents typically needed to solubilize the drug or polymer into a desirable composition is minimized or substantially reduced.
  • the drug carrier composition can be prepared with a greater amount of solids versus solvents, and still manufactured in a simple and cost-effective manner.
  • a relatively low amount of volatile solvent such as an ethyl acetate, can be used. This will greatly reduce drying times and the need to subject the carrier composition to elevated temperatures, and therefore minimize the chance of loss of desired volatile components, such as the drug.
  • This results in a carrier composition wherein the amount of drug necessary to achieve the desired permeation rate and profile can be significantly reduced from what would otherwise be needed, or be impossible to adequately load, as the loss of such drug is minimized.
  • Typical carrier compositions limit their overall solids content to about 40% to 50% as it is desirable or necessary to provide sufficient solvents to solubilize a sufficient amount of the active agent and/or solids therein, and still impart sufficient adhesive and cohesive properties to form a transdermal delivery system.
  • the agent carrier according to the invention is therefore prepared with a solids content from about 50% to 98% of the total weight of the carrier composition, or more preferably in the range of about 65% to about 85%.
  • the solids content and amount of the silicone-based adhesive can be increased to about 70% to about 80%, and 60% to about 80% weight percent, respectively, while the amount of acrylic adhesive can be reduced to about 1% to about 15% weight percent based on the dry weight of the total carrier composition.
  • Use of an acrylic adhesive as part of the carrier composition is preferred, particularly with silicone adhesives, because of its ability to solubilize and hold onto drug and still impart adhesive properties for attachment to other transdermal films/layers and skin or mucosa.
  • Such acrylic adhesives should not exceed a percent solids amount of greater than about 40% when used in the lower ranges described to retain their desired effect. When used alone or in blends, the percent solids of such acrylic adhesives would need to be substantially increased.
  • the amount of drug typically lost during processing to remove solvents from a carrier composition can be as high as 20%, and even 40% or more, depending on the functionality or capping of the adhesives or by virtue of the drug's relative volatility or reactivity with the other carrier components. Due to the relatively thick coating weights of carrier compositions needed to provide the necessary amount of drug and adhesive/cohesive properties to achieve the desired final product when dried, the manufacturing process required relatively prolonged exposure to elevated temperatures to substantially remove the solvents. A further benefit of the invention is the ability to increase processing speeds during manufacturing, since the coat weight of the carrier composition and/or the concentration of the drug can be reduced.
  • typical carrier compositions prepared with acrylic-based polymers or blend of polymers for a transdermal delivery device require coat weights of about 10 mg/cm 2 to achieve the desired drug loading and adhesive characteristics.
  • the coat weight of a carrier composition for delivering at least one drug at a similar flux may be reduced to about 5 mg/cm 2 , or about one-half the coat weight of prior systems.
  • the agent-carrier composition according to the invention containing significantly higher solids content and lower solvents, and capable of being coated to a backing or release liner at a lower coat weight, can be processed faster or with reduced exposure to elevated temperatures in order to minimize or prevent loss of drug or other desirable components, such as hydrophillic enhancers, but it cannot still achieve other necessary design and performance characteristics to be a transdermal delivery device.
  • Increasing per cent solids increases the "stiffness" of the carrier which can adversely affect the adhesive and cohesive properties required to function as a pressure-sensitive adhesive for topical application. Additionally, increasing per cent solids can decrease the ability of the carrier to adequately solubilize and hold onto the drug which further adversely affects pressure-sensitive properties as well as a controlled delivery rate or profile.
  • the carrier composition of the invention cannot adequately provide a controlled delivery, onset or profile for the drug, or the needed adhesive and cohesive properties, to be used by itself as a transdermal device until combined with a non-drug loaded polymeric and/or adhesive coating that is applied to either the backing or the release liner.
  • the polymeric coating 18 may comprise one or more of the polymers or adhesives described with reference to the drug carrier composition, generally with higher per cent solids, but contain no active agent during its exposure to elevated temperatures for solvent removal prior to being affixed to the drug carrier composition. Preferred are non-functional, acrylic-based adhesives.
  • the polymeric coating is disposed on either the backing or release liner and generally at a thickness ranging from about 2.5 mg/cm 2 to about 15 mg/cm 2 .
  • the carrier composition serves to absorb or attract and retain amounts of drug from the drug carrier composition, and subsequently release drug upon topical application of the transdermal system. This process further allows for potentially higher drug loading in the carrier composition, where desired or needed, for example to deliver therapeutically effective amounts over a longer period of delivery, since excess drug will be absorbed away thereby permitting the carrier composition to maintain its desired adhesive properties while still providing desired permeation rate and profile to be achieved.
  • the polymeric coating can further be prepared to selectively control the desired delivery rate, onset and profile for the drug by varying certain other physical characteristics.
  • the delivery rate, onset of delivery (lag time) and delivery profile of amphetamine base from the transdermal system may be selectively modulated by one or more of (a) increasing or decreasing the thickness or coat weight of per cm 2 (as applied to the backing or release liner of the system), (b) manipulating the moiety or functionality, and (c) manipulating the monomeric composition an/or ratios, of the acrylic-based non-drug loaded coating.
  • acrylic-based adhesives are used in the non-drug loaded coating
  • other polymers in combination, may be used provided such polymers have the ability to (a) incorporate and hold drug from the drug-loaded carrier composition after manufacture, (b) maintain contact/adhesion to both the carrier composition and either the backing film/layer or the release liner, preferably without the use of additional adhesives, (c) not degrade or interfere with stability of the drug, and (d) release or deliver the drug to the skin or mucosa after topical application of the transdermal system.
  • a pressure-sensitive adhesive carrier composition comprising a blend of (a) a solvent-based acrylic adhesive having a per cent solids concentration of about 30% to 50%, preferably polymerized with non-functional monomers, in an amount from about 60% to 80%, and more preferably from about 70% to about 80% and (b) a silicone-based adhesive having a per cent solids concentration of about 60% to about 90%, and more preferably from about 60% to about 80%, that is affixed to a non-drug acrlylic coating that is an adhesive and has a per cent solids concentration of about 30% to about 50%, preferably polymerized with non-functional and/or carboxy functional monomers, in an amount from about 3% to about 15%, and more preferably from about 3% to about 10%, wherein the amounts described are based on the dry weight of the total carrier composition.
  • Drug delivery is desired from such a system at a rate of about 0.1mg/cm 2 to about 10 mg/cm 2 and more preferably 0.1 mg/cm 2 to about0.6 mg/cm 2 , to deliver from about 2 to about 50 mg per 24 hours.
  • an enhancer can be incorporated into either the carrier composition or the polymeric coating, or both.
  • the term "enhancers” as used herein refers to substances used to increase permeability and/or accelerate the delivery of an active agent through the skin or mucosa, and include monhydric alcohols such as ethyl, isopropyl, butyl and benzyl alcohols; or dihydric alcohols such as ethylene glycol, diethylene glycol, or propylene glycol, dipropylene glycol and trimethylene glycol; or polyhydric alcohols such as glycerin, sorbitol and polyethylene glycol, which enhance drug solubility; polyethylene glycol ethers of aliphatic alcohols (such as cetyl, lauryl, oleyl and stearly) including polyoxyethylene (4) lauryl ether, polyoxyethylene (2) oleyl ether and polyoxyethylene (10) oleyl ether commercially available under the trademark BRIJ® 30, 93 and
  • enhancers include oleic and linoleic acids, triacetin, ascorbic acid, panthenol, butylated hydroxytoluene, tocopherol, tocopherol acetate, tocopheryl linoleate. If enhancers are incorporated into the transdermal system, the amount typically ranges up to about 30%, and preferably from about 0.1% to about 15%, by weight based on the dry weight of the total carrier composition.
  • Enhancers preferred for use in the drug carrier composition and polymeric coating differ by virtue of the their differing processing conditions.
  • Enhancers suitable for use with the polymeric coating are those with sufficiently high boiling points or lower volatile reactivity within the coating to withstand prolonged exposure to elevated processing temperatures employed to drive off the solvents therein, and include monovalent, saturated and unsaturated aliphatic and cycloaliphatic alcohols having 6 to 12 carbon atoms such as cyclohexanol, lauryl alcohol and the like; aliphatic and cycloaliphatic hydrocarbons such as mineral oils; cycloaliphatic and aromatic aldehydes and ketones such as cyclohexanone; N,N-di (lower alkyl) acetamides such as N,N-diethyl acetamide, N,N-dimethyl acetamide, N-(2-hydroxyethyl) acetamide, and the like; aliphatic and cycloaliphatic esters such as isopropyl myri
  • enhancers suitable for use with the drug carrier composition are those with lower boiling points or higher relative volatility or reactivity within the carrier composition since exposure to elevated processing temperatures is decreased, and therefore their loss, similar to drug loss, is decreased.
  • enhancers are well known in the art and examples include alcohols, propylene glycol, dipropylene glycol, butylene glycol, m- pyrol, oleates, and laurates, with propylene glycol being preferred.
  • additives include tackifying agents such as aliphatic hydrocarbons, mixed aliphatic and aromatic hydrocarbons, aromatic hydrocarbons, substituted aromatic hydrocarbons, hydrogenated esters, polyterpenes, silicone fluid, mineral oil and hydrogenated wood rosins.
  • tackifying agents such as aliphatic hydrocarbons, mixed aliphatic and aromatic hydrocarbons, aromatic hydrocarbons, substituted aromatic hydrocarbons, hydrogenated esters, polyterpenes, silicone fluid, mineral oil and hydrogenated wood rosins.
  • Additional additives include binders such as lecithin which "bind" the other ingredients, or rheological agents (thickeners) containing silicone such as fumed silica, reagent grade sand, precipitated silica, amorphous silica, colloidal silicon dioxide, fused silica, silica gel, quartz and particulate siliceous materials commercially available as Syloid®, Cabosil®, Aerosil®, and Whitelite®, for purposes of enhancing the uniform consistency or continuous phase of the composition or coating.
  • binders such as lecithin which "bind" the other ingredients
  • rheological agents such as fumed silica, reagent grade sand, precipitated silica, amorphous silica, colloidal silicon dioxide, fused silica, silica gel, quartz and particulate siliceous materials commercially available as Syloid®, Cabosil®, Aerosil®, and Whitelite®, for purposes of enhancing the uniform consistency or continuous phase of the composition or coating.
  • additives and excipients include diluents, stabilizers, fillers, clays, buffering agents, biocides, humectants, anti-irritants, antioxidants, preservatives, plasticizing agents, cross-linking agents, flavoring agents, colorants, pigments and the like. Such substances can be present in any amount sufficient to impart the desired properties to the composition or coating. Such additives or excipients are typically used in amounts up to 25%, and preferably from about 0.1 % to about 10%, by weight based on the dry weight of the total carrier composition.
  • Transdermal system 10 further employs release liners or removable/peelable covers and backings to protect and/or anchor the system or its components during manufacturing as described herein, or thereafter, and to enable handling and transportation.
  • the release liner is typically impermeable and occlusive, and must be compatible with the particular polymers or active agents so as not to interfere with the composition's ultimate application and therapeutic effect.
  • Some suitable materials that can be used, singularly, in combination, as laminates, films, or as coextrusions, to form the release liner are well known in the art.
  • the release liner is composed of a material which typically does not readily release (i.e., is not easily removed or separated from the coating or composition to which it is affixed), for example paper, a releasable material such as a silicone, Teflon®, or the like may be applied to the surface by any conventional means.
  • Preferred release liners are films commercially available from DuPont, Wilmington, Del., under the trademarks Mylar®, and fluropolymer (silicone) coated films commercially available from Rexam Release, Oak Brook, Ill. under the trademarks FL2000® and MRL2000®, and from 3M Corporation, St. Paul, Minn. Sold under the trademarks ScotchPak® such as 1022.
  • the backing is typically moisture impermeable and flexible but should be compatible with the particular polymers or active agents used so as not to interfere with the composition's ultimate application and therapeutic effect.
  • suitable materials that can be used, singularly, in combination, as laminates, films or as coextrusions, to form the backing layer 20 are also well known in the art and include films or sheets of polyethylene, polyester, polypropylene, polyurethane, polyolefin, polyvinyl alcohol, polyvinyl chloride, polyvinylidene, polyamide, vinyl acetate resins, BAREX®, ethylene/vinyl acetate copolymers, ethylene/ethylacrylate copolymers, metal-vapor deposited films or sheets thereof, rubber sheets or films, expanded synthetic resin sheets or films, non-woven fabrics, fabrics, knitted fabrics, clothes, foils and papers.
  • the backing layer 20 may generally have a thickness in the range of 2 to 1000 micrometers.
  • the backing layer 20 may be pigmented, for example colored to either match with or conversely easily distinguish from the site of application, and/or contain printing, labeling and other means of identification and/or traceability of the transdermal unit or system itself.
  • the backing layer 20 may further be made opaque or substantially opaque (i.e., preventing light or certain energy wavelengths from penetrating or passing through), such as by metallization, fillers, inks, dyes and the like, for purposes of protecting photosensitive active agents from degradation and/or preventing photoallergic reactions or irritations on the subject.
  • drug carrier composition 12 and the non-drug loaded polymeric and/or adhesive coating 18 are prepared separately and then combined.
  • the drug carrier and polymeric coating comprising the present invention can be prepared in any manner known to those of skill in the art.
  • transdermal system 10 An exemplary general method of preparing transdermal system 10 is as follows:
  • the release liner 22 may not be necessary if both the agent-carrier composition 12 and backing composite 16 are produced concomitantly, wherein attachment to each other could be performed after processing of each individually, such as in an in-line process, thereby avoiding step 3 above.
  • either the drug carrier composition 12 or the polymeric coating 18 may be an adhesive or pressure-sensitive adhesive, allowing pressure lamination to each other by their adhesive qualities.
  • a release liner 22 is employed in the manufacturing steps, it is preferable to affix it to the polymeric coating and not the drug carrier composition to prevent any further drug loss that could occur from winding into rolls and subsequent removal of such release liner, or the failure of release liner 22 to adhere to the drug carrier composition.
  • a separate adhesive may be used to (a) affix the backing composite 16 to the drug carrier composition 12 at the surface opposite the release liner 15 and/or (b) affix the polymeric coating or the drug carrier composition, depending on which is to be used as the point of topical application to the skin or mucosa, to either the backing film/layer or the release liner.
  • a non-woven drug permeable film/layer such as a polyester film
  • transdermal system to deliver certain drugs, such as amphetamine base, that are volatilized at or near ambient temperatures and/or degraded by exposure to atmospheric air, or that employ use of volatile enhancers, particular care should be employed to avoid prolonged processing times or exposure to air.
  • controlled manufacturing environments for example employing lower temperatures or pressures, modifying atmospheric gases present (such reduced carbon dioxide levels or using nitrogen in place of air), or modifying air or gas flow (such as during oven drying to remove solvents) at various stages during the process, may also be necessary or desirable.
  • the order of the processing steps, the amount of the ingredients, and the amount and time of agitation or mixing may be important process variables which will depend on the specific polymers, active agents, solvents or co-solvents, enhancers and additives and excipients used in the transdermal system. These factors can be adjusted by those skilled in the art, while keeping in mind the objects of achieving the interaction between the drug carrier composition and the non-drug loaded coating. It is believed that a number of other methods, for example, other methods of coating that are well-known in the art, such as Mayer rod, gravure, knife-over roll, extrusion, casting, calendaring and molding, or changing the order of certain steps, can be carried out and will also give desirable results.
  • Control transdermal delivery system that being a methylphenidate base transdermal delivery system (MethyPatch® produced by the assignee of the instant invention, Noven Pharmaceuticals, Inc.), having a known permeation rate, onset and profile.
  • All drug-loaded carrier compositions containing d-amphetamine were prepared using a blend of a non-functional, acrylic-based pressure sensitive adhesive having 75% solids in ethyl acetate and a silicone pressure-sensitive adhesive (BIO-PSA 7-4302).
  • the composition was coated onto a fluropolymer release liner and dried for in a 76° C oven to produce a pressure-sensitive adhesive carrier composition by dry weight of 5% acrylic adhesive, 75% silicone adhesive and 20% drug at a coat weight of about 5 mg/cm 2 .
  • All non-drug loaded acrylic-based adhesive coatings were prepared using the same acrylic adhesive used in preparing the drug-loaded carrier composition, which was coated onto a polyester backing and dried to a coat weight, for examples 1 and 2, to about 7.5 mg/cm 2 (example 3 being directed to varying coat weights as indicated below) before being pressure laminated to the drug carrier composition.
  • Determination of drug flux of the described formulations was conducted on a modified Franz Diffusion cell through a disc of stratum corneum obtained from human cadaver skin.
  • the transdermal system formulations were die-cut to punched, mounted on the disc, and placed on the cell, which contained an isotonic saline solution.
  • Example 1 two acrylic-based adhesive coatings were prepared that each contained two different non-functional monomers but in differing ratios, 1:1 and 8:2. No effect should have been observed based upon the non-reactive properties of non-functional acrylic adhesives with drugs. As seen in Fig. 3 , the effect of varying the monomeric ratios significantly influenced both delivery rate and profile, one being of a first-order type (fast onset and amount followed by depletion) and the other being near zero-order ("sustained").
  • Example 2 three acrylic-based adhesive coatings were prepared that had differing functionality, one being non-functional and the other two being carboxy-functional but with varying concentrations (4% and 8%) of the carboxy-functional monomer acrylic acid.
  • the non-functional acrylic coating imparted the fastest drug onset and higher drug depletion than either carboxy-functional coating.
  • carboxy-functional monomers decreased drug onset and provided a near zero-order delivery profile.
  • the addition of functional moiety to the acrylic coating in this case acidic functionality, increasingly diminishes both drug flux and onset with increasing carboxy concentrations, but can provide a near zero-order delivery rate profile.
  • Example 3 three acrylic-based adhesive coatings were prepared each using the acrylic adhesive coating described in Example 2 containing 8% carboxy-functionality but applied to the backing at three different thickness, about 2.5 mg/cm 2 , about 5 mg/cm 2 and about 7.5 mg/cm 2 .
  • the flux rate increases as the acrylic adhesive coating thickness decreases, while the delivery profile approaches near zero-order as the acrylic adhesive coating thickness increases.

Landscapes

  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Dermatology (AREA)
  • Veterinary Medicine (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Epidemiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Biomedical Technology (AREA)
  • Medical Informatics (AREA)
  • Hematology (AREA)
  • Anesthesiology (AREA)
  • Vascular Medicine (AREA)
  • Diabetes (AREA)
  • Endocrinology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Preparation (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Claims (42)

  1. Composition pour l'administration transdermique d'un médicament, destiné à être utilisé dans le traitement du trouble du déficit de l'attention, ou en présence d'une suppression de l'appétit, ladite composition comprenant
    une couche dorsale ;
    au moins une couche adhésive de revêtement comprenant au moins un polymère à base acrylique, une première surface de ladite au moins une couche adhésive de revêtement étant fixée à une surface de ladite couche dorsale ;
    au moins une couche d'une composition support, comprenant au moins un polymère à base acrylique, une première surface de ladite au moins une couche de composition support étant fixée à une deuxième surface de ladite au moins une couche adhésive de revêtement ; et
    une pellicule anti-adhésive détachable, fixée à une deuxième surface de ladite au moins une couche de la composition support, où au moins une couche de la composition support comprend une quantité thérapeutiquement efficace de d-amphétamine base ou de d-amphétamine base et de 1-amphétamine base incorporée dans au moins une couche de la composition support,
    et dans laquelle la masse surfacique, la composition en monomères et/ou la fonctionnalité de ladite couche adhésive de revêtement sont sélectionnées et adaptées pour ajuster le flux de médicaments provenant de ladite composition destinée à l'administration transdermique d'un médicament.
  2. Composition pour l'administration transdermique d'un médicament destinée à être utilisée selon la revendication 1, ladite composition étant un mélange d'au moins un polymère à base acrylique et d'au moins un deuxième polymère choisi dans le groupe comprenant les polymères à base de silicone, les caoutchoucs, les gommes, les polyisobutylènes, les polyvinyléthers, les polyuréthanes, les copolymères à blocs de styrène, les polymères styrène/butadiène, les copolymères d'amide à blocs polyéther, les copolymères éthylène/acétate de vinyle, les adhésifs à base d'acétate de vinyle, et les bioadhésifs.
  3. Composition pour l'administration transdermique d'un médicament destiné à être utilisé selon la revendication 2, dans laquelle ledit au moins deuxième polymère comprend un polymère à base de silicone.
  4. Composition pour l'administration transdermique d'un médicament destiné à être utilisé selon la revendication 2, dans laquelle le polymère à base acrylique est présent en une proportion de 2 à 95 % en poids par rapport au poids total sec de la composition support.
  5. Composition pour l'administration transdermique d'un médicament destinée à être utilisé selon la revendication 1, dans laquelle ledit polymère à base acrylique est présent en une proportion de 2 à 95 % en poids par rapport au poids total sec de la composition support.
  6. Composition pour l'administration transdermique d'un médicament destiné à être utilisé selon la revendication 5, dans laquelle ledit polymère à base acrylique est présent en une proportion de 2 à 85 % en poids par rapport au poids total sec de la couche de la composition support.
  7. Composition pour l'administration transdermique d'un médicament destiné à être utilisé selon la revendication 1, ladite couche de la composition support comprenant :
    (i) un premier polymère à base acrylique ayant une première fonctionnalité et un premier paramètre de solubilité ; et
    (ii) un deuxième polymère à base acrylique ayant une deuxième fonctionnalité et un deuxième paramètre de solubilité, la première et la deuxième fonctionnalités différant pour ce qui est de la quantité et du type des groupes fonctionnels, pour fournir une combinaison de polymères à base acrylique ayant une fonctionnalité nette proportionnelle au rapport entre le premier et le deuxième polymère à base acrylique utilisés, et étant présentes selon des proportions conduisant à un paramètre de solubilité net.
  8. Composition pour l'administration transdermique d'un médicament destiné à être utilisé selon la revendication 7, dans laquelle le premier polymère à base acrylique est présent en une quantité suffisante pour assurer le flux du ou des médicaments, dans la composition utilisée pour l'administration dermique d'un médicament, qui est supérieure à celui d'une composition uniquement à base du deuxième polymère à base acrylique.
  9. Composition pour l'administration transdermique d'un médicament pour l'utilisation selon la revendication 8, dans laquelle la quantité du deuxième polymère à base acrylique est comprise dans la plage de 5 à 95 % en poids, et la quantité du premier polymère à base acrylique est comprise dans la plage de 95 à 5 % en poids, toutes étant rapportées au poids total sec du polymère.
  10. Composition pour administration transdermique d'un médicament pour l'utilisation selon la revendication 9, dans laquelle la quantité du deuxième polymère à base acrylique est comprise dans la plage de 20 à 75 % en poids et la quantité du premier polymère à base acrylique est comprise dans la plage de 75 à 20 % en poids, toutes par rapport au poids total sec du polymère.
  11. Composition pour l'administration transdermique d'un médicament destiné à être utilisé selon la revendication 7, dans laquelle le premier polymère à base acrylique n'a pour ainsi dire aucun groupe fonctionnel, et le deuxième polymère à base acrylique possède des groupes fonctionnels prédéterminés.
  12. Composition pour l'administration transdermique d'un médicament destiné à être utilisé selon la revendication 11, dans laquelle le deuxième polymère à base acrylique comprend des groupes fonctionnels carboxyle et/ou hydroxy.
  13. Composition pour l'administration transdermique d'un médicament pour l'utilisation selon la revendication 11, dans laquelle le deuxième polymère à base acrylique est présent en une quantité assurant une concentration accrue à la saturation dans la composition pour l'administration dermique d'un médicament, qui est supérieure à celle d'une composition à base uniquement du premier polymère à base acrylique.
  14. Composition pour l'administration transdermique d'un médicament pour l'utilisation selon la revendication 7, dans laquelle les groupes fonctionnels sont fournis par des motifs monomères contenant des groupes fonctionnels qui sont incorporés dans le deuxième polymère à base acrylique en une quantité de 0,1 à 20 % en poids par rapport au poids sec du deuxième polymère à base acrylique.
  15. Composition pour administration transdermique d'un médicament pour l'utilisation selon la revendication 14, dans laquelle les monomères fonctionnels sont incorporés dans le deuxième polymère à base acrylique en une quantité de 0,1 à 8 % en poids par rapport au poids sec du deuxième polymère à base acrylique.
  16. Composition pour l'administration transdermique d'un médicament pour l'utilisation selon la revendication 7, dans laquelle les au moins deux polymères ne contiennent sensiblement que le premier et le deuxième polymères à base acrylique.
  17. Composition pour l'administration transdermique d'un médicament destiné à être utilisé selon la revendication 7, dans laquelle le deuxième polymère à base acrylique comprend des groupes fonctionnels carboxyl.
  18. Composition pour l'administration transdermique d'un médicament destiné à être utilisé selon la revendication 17, dans laquelle le polymère à base acrylique à fonctionnalité carboxyle comprend 0,1 à 10 % en poids de motifs monomères à fonctionnalité carboxyle.
  19. Composition pour l'administration transdermique d'un médicament pour l'utilisation selon la revendication 18, dans laquelle le polymère à base acrylique à fonctionnalité carboxyle est un polymère à base acrylique d'acétate de vinyle réticulé.
  20. Composition pour l'administration transdermique d'un médicament pour l'utilisation selon la revendication 1, dans laquelle ladite couche de revêtement adhésive comprend :
    (i) un premier polymère à base acrylique ayant une première fonctionnalité ; et
    (ii) un deuxième polymère à base acrylique ayant une deuxième fonctionnalité, la première et la deuxième fonctionnalité différant en quantité et en type des groupes fonctionnels, pour fournir une combinaison de polymères à base acrylique ayant une fonctionnalité nette proportionnelle au rapport entre le premier et le deuxième polymère à base acrylique utilisés.
  21. Composition pour l'administration transdermique d'un médicament destiné à être utilisé selon la revendication 20, dans laquelle la quantité du deuxième polymère à base acrylique est comprise dans la plage de 5 à 95 % en poids, et la quantité du premier polymère à base acrylique est comprise dans la plage de 95 à 5 % en poids, toutes par rapport au poids total sec du polymère.
  22. Composition pour l'administration transdermique d'un médicament destiné à être utilisé selon la revendication 20, dans laquelle la quantité du deuxième polymère à base acrylique est comprise dans la plage de 20 à 75 % en poids, et la quantité du premier polymère à base acrylique est comprise dans la plage de 75 à 20 % en poids, toutes par rapport au poids total sec du polymère.
  23. Composition pour l'administration transdermique d'un médicament destiné à être utilisé selon la revendication 20, dans laquelle le premier polymère à base acrylique n'a sensiblement aucun groupe fonctionnel, et le deuxième polymère à base acrylique a des groupes fonctionnels prédéterminés.
  24. Composition pour l'administration transdermique d'un médicament destiné à être utilisé selon la revendication 23, dans laquelle le deuxième polymère à base acrylique comprend des groupes fonctionnels carboxyle et/ou hydroxy.
  25. Composition pour l'administration transdermique d'un médicament destiné à être utilisé selon la revendication 20, dans laquelle les groupes fonctionnels sont fournis par des motifs monomères contenant des groupes fonctionnels qui sont incorporés dans le deuxième polymère à base acrylique en une quantité de 0,1 à 20 % en poids par rapport au poids sec du deuxième polymère à base acrylique.
  26. Composition pour l'administration transdermique d'un médicament destiné à être utilisé selon la revendication 25, dans laquelle les monomères fonctionnels sont incorporés dans le deuxième polymère à base acrylique en une quantité de 0,1 à 8 % en poids par rapport au poids sec du deuxième polymère à base acrylique.
  27. Composition pour l'administration transdermique d'un médicament pour l'utilisation selon la revendication 20, dans laquelle les au moins deux polymères ne contiennent sensiblement que le premier et le deuxième polymère à base acrylique.
  28. Composition pour l'administration transdermique d'un médicament destiné à être utilisé selon la revendication 20, dans laquelle le deuxième polymère à base acrylique comprend des groupes fonctionnels carboxyle.
  29. Composition pour l'administration transdermique d'un médicament destiné à être utilisé selon la revendication 28, dans laquelle le polymère à base acrylique à fonctionnalité carboxyle comprend 0,1 à 10 % en poids de motifs monomères à fonctionnalité carboxyle.
  30. Composition pour l'administration transdermique d'un médicament destiné à être utilisé selon la revendication 29, dans laquelle le polymère à base acrylique à fonctionnalité carboxyle est un polymère à base acrylique d'acétate de vinyle réticulé.
  31. Composition pour l'administration transdermique d'un médicament destiné à être utilisé selon la revendication 1, dans laquelle ladite couche adhésive de revêtement comprend un mélange :
    (i) d'un polymère à base acrylique ; et
    (ii) d'au moins un deuxième polymère choisi dans le groupe consistant en les polymères à base de silicone, les caoutchoucs, les gommes, les polyisobutylènes, le polyvinyléthers, les polyuréthanes, les copolymères à blocs de styrène, les polymères styrène/butadiène, les copolymères d'amide à blocs polyéthers, les copolymères éthylène/acétate de vinyle ; les adhésifs à base d'acétate de vinyle, et les bio-adhésifs.
  32. Composition pour l'administration transdermique d'un médicament destiné à être utilisé selon la revendication 31, dans laquelle ledit deuxième polymère comprend un polymère à base de silicone.
  33. Composition pour l'administration transdermique d'un médicament destiné à être utilisé selon la revendication 1, dans laquelle ladite couche de revêtement adhésive a une masse surfacique de 2,5 à 15 mg/cm2.
  34. Composition pour l'administration transdermique d'un médicament destiné à être utilisé selon la revendication 33, dans laquelle ladite couche de revêtement adhésive a une masse surfacique de 2,5 à 7,5 mg/cm2.
  35. Composition pour l'administration transdermique d'un médicament destiné à être utilisé selon la revendication 1, dans laquelle ladite couche de revêtement adhésive a une masse surfacique d'environ 5 mg/cm2.
  36. Composition pour l'administration transdermique d'un médicament destiné à être utilisé selon la revendication 1, dans laquelle ledit revêtement adhésif comprend au moins un polymère à base acrylique, et dans laquelle ledit polymère à base acrylique est composé d'au moins 50 % en poids d'un acrylate ou d'un acrylate d'alkyle monomère, de 0 à 20 % d'un monomère fonctionnel copolymérisable avec l'acrylate, et de 0 à 40 % d'autres monomères.
  37. Composition pour l'administration transdermique d'un médicament destiné à être utilisé selon la revendication 36, dans laquelle ledit acrylate ou ledit acrylate d'alkyle monomère comprend l'acide acrylique, l'acide méthacrylique, l'acrylate de butyle, le méthacrylate de butyle, l'acrylate d'hexyle, le méthacrylate d'hexyle, l'acrylate de 2-éthylbutyle, le méthacrylate de 2-éthylbutyle, l'acrylate d'isooctyle, le méthacrylate d'isooctyle, l'acrylate de 2-éthylhexyle, le méthacrylate de 2-éthylhexyle, l'acrylate de décyle, le méthacrylate de décyle, l'acrylate de dodécyle, le méthacrylate de dodécyle, l'acrylate de tridécyle et le méthacrylate de tridécyle.
  38. Dispositif pour l'administration transdermique d'un médicament destiné à être utilisé selon la revendication 37, dans lequel ledit monomère fonctionnel est un monomère choisi dans le groupe consistant en l'acide méthacrylique, l'acide maléique, l'anhydride maléique, l'acrylate d'hydroxyéthyle, l'acrylate hydroxypropylique, l'acrylamide, le diméthylacrylamide, l'acrylonitrile, l'acrylate de diméthylaminoéthyle, le méthacrylate de diméthylaminoéthyle, l'acrylate de tert-butylaminoéthyle, le méthacrylate de tert-butylaminoéthyle, l'acrylate de méthoxyéthyle et le méthacrylate de méthoxyéthyle.
  39. Procédé de production de la composition pour l'administration transdermique d'un médicament selon la revendication 1, comprenant les étapes suivantes :
    mélange intime et uniforme, dans un récipient, de quantités appropriées du ou des polymères, du ou des adhésifs, du ou des solvants, du ou des co-solvants, du ou des renforçateurs, du ou des additifs et/ou excipients pour former la couche de la composition support ;
    coulée de ladite composition support sur une pellicule anti-adhésive, et exposition à des températures élevées de ladite couche adhésive coulée, pour éliminer les solvants de traitement volatils ;
    contre-collage dudit revêtement adhésif sur une première pellicule anti-adhésive qui est appliquée sur la surface opposée à la pellicule de support ;
    mélange intime et uniforme, de quantités appropriées d'un ou plusieurs médicaments, polymères, adhésifs, solvants, co-solvants, renforçateurs, additifs et/ou excipients dans un récipient, pour former la couche de la composition support ;
    coulée de ladite composition support sur une deuxième pellicule anti-adhésive ;
    détachement de la première pellicule anti-adhésive, et fixation de ladite couche de revêtement adhésive sur ladite couche de la composition support.
  40. Procédé selon la revendication 39, dans lequel ladite composition support est exposée à des températures élevées pour éliminer les solvants de traitement volatils après coulée sur ladite deuxième pellicule anti-adhésive.
  41. Procédé de fabrication d'une composition pour l'administration transdermique d'un médicament selon la revendication 1, comprenant la formation d'une composition comprenant :
    (i) une couche de support ;
    (ii) au moins une couche de revêtement adhésive, une première surface de ladite au moins une couche de revêtement adhésive étant fixée à une surface de ladite couche de support ;
    (iii) au moins une couche d'une composition support comprenant une quantité thérapeutiquement efficace de d-amphétamine base ou de d-amphétamine base et de 1-amphétamine base, une première surface de ladite au moins couche de la composition support étant fixée à une deuxième surface de ladite au moins une couche de revêtement adhésive ; et
    (iv) une pellicule anti-adhésive fixée à une deuxième surface de ladite au moins une couche de la composition support
    ledit procédé comprenant l'adaptation sélective de ladite couche de revêtement adhésive par modification de la masse surfacique, de la composition en monomères ou de la fonctionnalité de ladite couche de revêtement support pour réguler le flux du médicament à partir de ladite composition destinée à l'administration transdermique d'un médicament.
  42. Composition pour l'administration transdermique d'un médicament pour l'utilisation selon l'une quelconque des revendications 1 à 38, ladite composition comprenant de la d-amphétamine base et de la 1-amphétamine base.
EP04810038.2A 2003-10-28 2004-10-28 Dispositif d'administration de medicaments par voie transdermique Expired - Lifetime EP1682061B1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US51530603P 2003-10-28 2003-10-28
PCT/US2004/035556 WO2005042055A2 (fr) 2003-10-28 2004-10-28 Compositions et procedes de controle de perte et d'administration de medicaments dans des systemes d'administration de medicaments par voie transdermique

Publications (3)

Publication Number Publication Date
EP1682061A2 EP1682061A2 (fr) 2006-07-26
EP1682061A4 EP1682061A4 (fr) 2011-12-07
EP1682061B1 true EP1682061B1 (fr) 2017-03-15

Family

ID=34549389

Family Applications (1)

Application Number Title Priority Date Filing Date
EP04810038.2A Expired - Lifetime EP1682061B1 (fr) 2003-10-28 2004-10-28 Dispositif d'administration de medicaments par voie transdermique

Country Status (19)

Country Link
US (3) US8703175B2 (fr)
EP (1) EP1682061B1 (fr)
JP (2) JP2007509951A (fr)
KR (1) KR20060114338A (fr)
CN (1) CN100457064C (fr)
AU (1) AU2004285505B2 (fr)
BR (1) BRPI0416063A (fr)
CA (1) CA2542778C (fr)
ES (1) ES2626784T3 (fr)
GE (1) GEP20084561B (fr)
IL (1) IL174894A0 (fr)
ME (2) MEP23508A (fr)
NO (1) NO20062434L (fr)
NZ (1) NZ546992A (fr)
RS (1) RS20060332A (fr)
RU (1) RU2356580C2 (fr)
UA (1) UA84303C2 (fr)
WO (1) WO2005042055A2 (fr)
ZA (1) ZA200603300B (fr)

Families Citing this family (71)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ATE288256T1 (de) * 1999-01-14 2005-02-15 Noven Pharma Dermale zusammensetzungen
US20030170195A1 (en) * 2000-01-10 2003-09-11 Noven Pharmaceuticals, Inc. Compositions and methods for drug delivery
US6682757B1 (en) * 2000-11-16 2004-01-27 Euro-Celtique, S.A. Titratable dosage transdermal delivery system
WO2005025549A2 (fr) * 2003-09-10 2005-03-24 Noven Pharmaceuticals, Inc. Dispositif multicouche d'administration transdermique de medicaments
CA2546200A1 (fr) * 2003-11-18 2005-06-02 3M Innovative Properties Company Compositions d'administration medicamenteuse transdermique renfermant de l'olanzapine
EP1802258A4 (fr) 2004-09-13 2015-09-23 Chrono Therapeutics Inc Administration de medicament transdermique biosynchrone
US8252321B2 (en) 2004-09-13 2012-08-28 Chrono Therapeutics, Inc. Biosynchronous transdermal drug delivery for longevity, anti-aging, fatigue management, obesity, weight loss, weight management, delivery of nutraceuticals, and the treatment of hyperglycemia, alzheimer's disease, sleep disorders, parkinson's disease, aids, epilepsy, attention deficit disorder, nicotine addiction, cancer, headache and pain control, asthma, angina, hypertension, depression, cold, flu and the like
US8343538B2 (en) 2004-10-08 2013-01-01 Noven Pharmaceuticals, Inc. Compositions and methods for controlling the flux of a drug from a transdermal drug delivery systems
WO2006041911A2 (fr) 2004-10-08 2006-04-20 Noven Pharmaceuticals, Inc. Dispositif d'administration transdermique de medicaments contenant des polymeres acryliques
KR100764679B1 (ko) * 2005-07-22 2007-10-09 익수제약 주식회사 파록세틴을 함유하는 경피투여용 패취제
CA2629046C (fr) * 2005-12-13 2014-04-08 Biodelivery Sciences International, Inc. Dispositif resistant aux abus pour l'administration transmucosale de medicaments
DE102006026060B4 (de) * 2006-01-12 2013-01-31 Lts Lohmann Therapie-Systeme Ag Transdermales Therapeutisches System enthaltend als Wirkstoff Nikotin und Verfahren zur Herstellung solcher Systeme
EP2010156B1 (fr) 2006-03-24 2016-11-16 Auxilium International Holdings, Inc. Compositions stabilisees contenant des medicaments labiles alcalins
CN101489756B (zh) * 2006-03-24 2013-08-07 奥克思利尤姆国际控股公司 热熔挤出层压材料的制备方法
WO2007112287A2 (fr) * 2006-03-24 2007-10-04 Auxilium Pharmaceuticals, Inc. Compositions transdermiques extrudées à chaud contenant de la testostérone
CN103550136B (zh) 2006-07-21 2016-04-13 生物递送科学国际公司 吸收增强的经粘膜递送装置
US20090246155A1 (en) * 2006-12-05 2009-10-01 Landec Corporation Compositions and methods for personal care
CA2670749A1 (fr) * 2006-12-05 2008-06-12 Landec Corporation Administration de medicaments
US8399007B2 (en) * 2006-12-05 2013-03-19 Landec Corporation Method for formulating a controlled-release pharmaceutical formulation
US20100004124A1 (en) * 2006-12-05 2010-01-07 David Taft Systems and methods for delivery of materials for agriculture and aquaculture
US20090263346A1 (en) * 2006-12-05 2009-10-22 David Taft Systems and methods for delivery of drugs
NZ582565A (en) 2007-07-10 2012-07-27 Agile Therapeutics Inc Dermal delivery device with in situ seal
WO2009026133A2 (fr) * 2007-08-17 2009-02-26 Alza Corporation Système d'administration transdermique de bisoprolol
WO2009026135A2 (fr) * 2007-08-17 2009-02-26 Alza Corporation Système d'administration transdermique commandée de bisoprolol
US8114883B2 (en) * 2007-12-04 2012-02-14 Landec Corporation Polymer formulations for delivery of bioactive materials
DE102008013701A1 (de) * 2008-03-11 2009-09-17 Lts Lohmann Therapie-Systeme Ag Transdermales Therapeutisches System mit stabilisierter Membran
US8231906B2 (en) 2008-07-10 2012-07-31 Noven Pharmaceuticals, Inc. Transdermal estrogen device and delivery
CA2733265A1 (fr) * 2008-09-30 2010-04-08 Teikoku Pharma Usa, Inc. Compositions de donepezil a administration transdermique etendue et leurs procedes d'utilisation
RU2497679C2 (ru) 2008-10-02 2013-11-10 Милан Инк. Способ получения многослойного клеящегося ламинированного материала
JP5706882B2 (ja) * 2009-04-17 2015-04-22 スリーエム イノベイティブ プロパティズ カンパニー シリコーンゲル接着剤構成体
KR101670379B1 (ko) * 2009-07-31 2016-10-28 (주)씨엘팜 니코틴 경피 전달 패취
CA2841785A1 (fr) 2011-07-06 2013-01-10 The Parkinson's Institute Compositions et methodes de traitement de symptomes chez des patients atteints de la maladie de parkinson
AU2012296346A1 (en) 2011-08-18 2014-04-03 Biodelivery Sciences International, Inc. Abuse-resistant mucoadhesive devices for delivery of buprenorphine
US9901539B2 (en) 2011-12-21 2018-02-27 Biodelivery Sciences International, Inc. Transmucosal drug delivery devices for use in chronic pain relief
FR2987561B1 (fr) * 2012-03-02 2014-04-11 Pf Medicament Dispositif transdermique comprenant des micro-particules poreuses
US9717697B2 (en) * 2012-10-15 2017-08-01 Noven Pharmaceuticals, Inc. Compositions and methods for the transdermal delivery of methylphenidate
JP2015535253A (ja) 2012-10-25 2015-12-10 ノーヴェン ファーマシューティカルズ インコーポレイテッド アンフェタミンの組成物及びアンフェタミンを経皮送達する方法
CN103845220B (zh) * 2012-12-04 2017-09-01 日绊株式会社 贴附剂
TW201431554A (zh) 2012-12-28 2014-08-16 Noven Pharma 左炔諾孕酮（ｌｅｖｏｎｏｒｇｅｓｔｒｅｌ）及乙烯雌二醇之經皮藥物遞送系統
CA2896055C (fr) * 2012-12-28 2021-02-16 Noven Pharmaceuticals, Inc. Compositions et procedes pour l'administration transdermique d'amphetamine et de clonidine
EP2938335B1 (fr) 2012-12-28 2021-03-17 Noven Pharmaceuticals, INC. Compositions multipolymères pour l'administration transdermique de médicaments
US20140188056A1 (en) * 2012-12-28 2014-07-03 Noven Pharmaceuticals, Inc. Compositions and methods for transdermal delivery of non-steroidal anti-inflammatory agents
US20140276483A1 (en) * 2013-03-14 2014-09-18 Noven Pharmaceuticals, Inc. Transdermal methylphenidate compositions with acrylic block copolymers
WO2014159582A1 (fr) * 2013-03-14 2014-10-02 Noven Pharmaceuticals, Inc Compositions transdermiques d'amphétamine au moyen de copolymère à bloc acrylique
AR095259A1 (es) 2013-03-15 2015-09-30 Noven Pharma Composiciones y métodos para la administración transdérmica de fármacos de amina terciaria
AR095260A1 (es) * 2013-03-15 2015-09-30 Noven Pharma Composiciones de anfetaminas transdérmicas estables y métodos de fabricación
CN103432104B (zh) * 2013-08-09 2015-10-28 大连理工大学 一种含有普拉克索的透皮贴剂
WO2015054061A1 (fr) * 2013-10-07 2015-04-16 Teikoku Pharma Usa, Inc. Procédés et compositions pour l'administration transdermique d'une quantité non sédative de dexmédétomidine
ES2856189T3 (es) 2013-10-07 2021-09-27 Teikoku Pharma Usa Inc Métodos y composiciones para el tratamiento del trastorno de hiperactividad por déficit de atención, ansiedad e insomnio utilizando composiciones transdérmicas de dexmedetomidina
WO2015087927A1 (fr) * 2013-12-12 2015-06-18 久光製薬株式会社 Patch avec élément de couverture et kit de patch avec élément de couverture
TWI674900B (zh) * 2013-12-23 2019-10-21 諾芬藥品公司 用於經皮輸送安非他命之組合物及方法
AR101358A1 (es) * 2014-07-31 2016-12-14 Noven Pharma Composiciones de polímeros acrílicos que contienen siliconas para la administración transdérmica de fármacos
JP2018511355A (ja) 2015-01-28 2018-04-26 クロノ セラピューティクス インコーポレイテッドＣｈｒｏｎｏ Ｔｈｅｒａｐｅｕｔｉｃｓ Ｉｎｃ． 薬剤送達方法及びシステム
EP3250618A4 (fr) * 2015-01-29 2018-07-18 Dow Silicones Corporation Compositions d'acrylate de silicone et procédés pour les préparer
MX371044B (es) 2015-02-06 2020-01-13 Noven Pharma Adhesivos sensibles a la presión para suministro transdérmico de fármaco.
US10406116B2 (en) 2015-02-06 2019-09-10 Noven Pharmaceuticals, Inc. Pressure-sensitive adhesives for transdermal drug delivery
JP2018511127A (ja) 2015-03-12 2018-04-19 クロノ セラピューティクス インコーポレイテッドＣｈｒｏｎｏ Ｔｈｅｒａｐｅｕｔｉｃｓ Ｉｎｃ． 渇望入力及び支援システム
KR101897174B1 (ko) 2016-08-17 2018-09-12 (주)오스힐 연부조직질환 치료용 경피약물전달 촉진장치
CA3003460A1 (fr) * 2016-10-07 2018-04-12 Transwell Biotech Co., Ltd. Systeme d'administration transdermique de pramipexole et ses utilisations
WO2018115001A1 (fr) 2016-12-20 2018-06-28 Lts Lohmann Therapie-Systeme Ag Système thérapeutique transdermique comportant de l'asénapine
JP7149287B2 (ja) 2016-12-20 2022-10-06 エルテーエス ローマン テラピー－ジステーメ アーゲー アセナピンおよびポリシロキサンまたはポリイソブチレンを含有する経皮治療システム
EP3573604A4 (fr) * 2016-12-29 2020-07-22 Pure Ratios Holdings, Inc. Système d'administration transdermique modulaire et procédés de fabrication et d'utilisation associés
US11285306B2 (en) 2017-01-06 2022-03-29 Morningside Venture Investments Limited Transdermal drug delivery devices and methods
CA3067938A1 (fr) 2017-06-26 2019-01-03 Lts Lohmann Therapie-Systeme Ag Systeme therapeutique transdermique contenant de l'asenapine et un polymere hybride acrylique de type silicone
JP7420797B2 (ja) 2018-05-29 2024-01-23 モーニングサイド ベンチャー インベストメンツ リミテッド 薬剤送達の方法及びシステム
US11648213B2 (en) 2018-06-20 2023-05-16 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system containing asenapine
WO2020092990A1 (fr) * 2018-11-02 2020-05-07 Eastern Virginia Medical School Compositions pharmaceutiques et procédés de fabrication d'une formulation de timbre pour administration transdermique
EP4003256A4 (fr) * 2019-07-30 2023-05-24 Kai P. Leung Composite stratifié pour le traitement et la prévention de cicatrices
AR124578A1 (es) * 2021-01-07 2023-04-12 Noven Pharma Compuestos de carbamato de anfetamina y métodos relacionados
US11559501B2 (en) * 2021-01-07 2023-01-24 Noven Pharmaceuticals, Inc. Transdermal amphetamine compositions with low levels of carbamate
WO2023240478A1 (fr) * 2022-06-15 2023-12-21 Dow Silicones Corporation Composition de revêtement pelable et son utilisation

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995008324A1 (fr) * 1993-09-22 1995-03-30 Lts Lohmann Therapie-Systeme Gmbh Pansement contenant des principes actifs volatils susceptible d'etre produit sans solvants

Family Cites Families (56)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5843368B2 (ja) * 1980-10-30 1983-09-27 日東電工株式会社 消炎鎮痛貼付剤
GB2105990B (en) * 1981-08-27 1985-06-19 Nitto Electric Ind Co Adhesive skin patches
US4559222A (en) * 1983-05-04 1985-12-17 Alza Corporation Matrix composition for transdermal therapeutic system
US4591622A (en) * 1984-10-29 1986-05-27 Dow Corning Corporation Silicone pressure-sensitive adhesive process and product thereof
US4655767A (en) * 1984-10-29 1987-04-07 Dow Corning Corporation Transdermal drug delivery devices with amine-resistant silicone adhesives
US4584355A (en) * 1984-10-29 1986-04-22 Dow Corning Corporation Silicone pressure-sensitive adhesive process and product with improved lap-shear stability-I
US4585836A (en) * 1984-10-29 1986-04-29 Dow Corning Corporation Silicone pressure-sensitive adhesive process and product with improved lap-shear stability-II
US4938759A (en) * 1986-09-02 1990-07-03 Alza Corporation Transdermal delivery device having a rate controlling adhesive
US4911707A (en) * 1987-02-13 1990-03-27 Ciba-Geigy Corporation Monolithic user-activated transdermal therapeutic system
US4746515A (en) * 1987-02-26 1988-05-24 Alza Corporation Skin permeation enhancer compositions using glycerol monolaurate
US4983395A (en) * 1987-11-12 1991-01-08 Theratech Inc. Device for administering an active agent to the skin or mucosa
US4915950A (en) * 1988-02-12 1990-04-10 Cygnus Research Corporation Printed transdermal drug delivery device
US4994267A (en) * 1988-03-04 1991-02-19 Noven Pharmaceuticals, Inc. Transdermal acrylic multipolymer drug delivery system
US5656286A (en) * 1988-03-04 1997-08-12 Noven Pharmaceuticals, Inc. Solubility parameter based drug delivery system and method for altering drug saturation concentration
US4994278A (en) * 1988-03-04 1991-02-19 Noven Pharmaceuticals, Inc. Breathable backing
US5474783A (en) * 1988-03-04 1995-12-12 Noven Pharmaceuticals, Inc. Solubility parameter based drug delivery system and method for altering drug saturation concentration
US5446070A (en) * 1991-02-27 1995-08-29 Nover Pharmaceuticals, Inc. Compositions and methods for topical administration of pharmaceutically active agents
DE3905050A1 (de) * 1989-02-18 1990-08-30 Lohmann Therapie Syst Lts Therapeutisches system zur verzoegerten und gesteuerten transdermalen oder transmucosalen verabreichung von wirkstoffen (ii)
US5262165A (en) * 1992-02-04 1993-11-16 Schering Corporation Transdermal nitroglycerin patch with penetration enhancers
US5271940A (en) * 1989-09-14 1993-12-21 Cygnus Therapeutic Systems Transdermal delivery device having delayed onset
WO1992009252A1 (fr) * 1990-11-28 1992-06-11 Sano Corporation Procede et dispositif destines a traiter le tabagisme
US5633009A (en) * 1990-11-28 1997-05-27 Sano Corporation Transdermal administration of azapirones
CA2075517C (fr) * 1992-04-01 1997-03-11 John Wick Piece transdermique incorporant une pellicule de polymeres incorporee a l'aide d'un agent actif
JP2960832B2 (ja) * 1992-05-08 1999-10-12 ペルマテック テクノロジー アクチェンゲゼルシャフト エストラジオールの投与システム
US5622944A (en) * 1992-06-12 1997-04-22 Affymax Technologies N.V. Testosterone prodrugs for improved drug delivery
US5462746A (en) * 1992-11-02 1995-10-31 Lts Lohmann Therapie-Systeme Gmbh & Co. Kg Patch for transdermal administration of volatile pharmaceutically active ingredients of chemically basic nature and a process for preparation
GB2273044B (en) * 1992-12-02 1997-04-09 Pacific Chem Co Ltd Medicinal patches for percutaneous administration
JP2569396B2 (ja) * 1992-12-04 1997-01-08 株式会社太平洋 経皮投与型薬物用貼付剤
DK0695177T3 (da) * 1993-04-20 1998-09-28 Hexal Ag Plaster indeholdende aktivt stof
US5762952A (en) * 1993-04-27 1998-06-09 Hercon Laboratories Corporation Transdermal delivery of active drugs
US5567488A (en) * 1993-09-16 1996-10-22 The Dow Chemical Company Multilayer barrier film for transdermal drug delivery system and ostomy applications
US5723145A (en) * 1993-09-30 1998-03-03 Takiron Co., Ltd. Transdermal absorption preparation
DE4405898A1 (de) * 1994-02-18 1995-08-24 Schering Ag Transdermale therapeutische Systeme enthaltend Sexualsteroide
US5474787A (en) * 1994-10-21 1995-12-12 The Wm. Wrigley Jr. Company Chewing gum containing a lecithin/glycerol triacetate blend
FR2728463A1 (fr) * 1994-12-21 1996-06-28 Lhd Lab Hygiene Dietetique Systeme transdermique d'administration simultanee de plusieurs principes actifs
EP0833671A2 (fr) * 1995-06-07 1998-04-08 Noven Pharmaceuticals, Inc. Compositions transdermiques contenant des medicaments de faible poids moleculaire liquides a temperature ambiante
US5906830A (en) * 1995-09-08 1999-05-25 Cygnus, Inc. Supersaturated transdermal drug delivery systems, and methods for manufacturing the same
US5902603A (en) * 1995-09-14 1999-05-11 Cygnus, Inc. Polyurethane hydrogel drug reservoirs for use in transdermal drug delivery systems, and associated methods of manufacture and use
FR2749586B1 (fr) * 1996-06-11 1998-08-07 Hoechst Marion Roussel Inc Nouveaux dispositifs destines a l'administration transdermique de la trimegestone, leur procede de preparation et leur application a titre de medicaments
WO1998034615A1 (fr) * 1997-02-07 1998-08-13 Synapse Pharmaceuticals International, Inc. Composition pharmaceutique contenant de l'oxime, pour le traitement de dysfonctionnement synaptique
DE19738855C2 (de) * 1997-09-05 2001-01-04 Lohmann Therapie Syst Lts Transdermales therapeutisches System mit haftklebender Reservoirschicht und unidirektional elastischer Rückschicht
ATE314092T1 (de) * 1997-09-26 2006-01-15 Noven Pharma Biologische kleber und verfahren zur topischen verabreichung von wirkstoffen
US6210705B1 (en) * 1997-12-15 2001-04-03 Noven Pharmaceuticals, Nc. Compositions and methods for treatment of attention deficit disorder and attention deficit/hyperactivity disorder with methylphenidate
AU778992B2 (en) 1998-12-07 2004-12-23 Agi Therapeutics Research Limited Transdermal patch for delivering volatile liquid drugs
EP1449527A3 (fr) 1998-12-07 2004-09-08 Elan Pharma International Limited Patch transdermique pour administrer un principe actif volatile
US20030170195A1 (en) * 2000-01-10 2003-09-11 Noven Pharmaceuticals, Inc. Compositions and methods for drug delivery
KR20010036685A (ko) 1999-10-11 2001-05-07 김윤 펜타닐을 함유하는 매트릭스형 경피투여제
DE19950066A1 (de) 1999-10-16 2001-04-26 Lohmann Therapie Syst Lts Transdermales therapeutisches System mit einem Gehalt an Tulobuterol-hydrochlorid zur Verabreichung des Bronchodilatators Tulobuterol über die Haut
JP4841781B2 (ja) * 1999-11-24 2011-12-21 アジル・セラピューティクス・インコーポレイテッド 改良された経皮的避妊薬送達系および方法
DE60119140T2 (de) * 2000-09-24 2007-02-08 3M Innovative Properties Co., St. Paul Trocknungsverfahren zur selektiven entfernung flüchtiger bestandteile aus nassen beschichtungen
AU3946402A (en) * 2000-11-01 2002-05-27 Sention Inc Methods and compositions for regulating memory consolidation
US6448303B1 (en) * 2000-12-29 2002-09-10 National Starch And Chemical Investment Holding Corporation Hot melt adhesives for dermal application
JP4323138B2 (ja) * 2002-06-05 2009-09-02 日東電工株式会社 経皮吸収型製剤およびその製造方法
WO2005025549A2 (fr) * 2003-09-10 2005-03-24 Noven Pharmaceuticals, Inc. Dispositif multicouche d'administration transdermique de medicaments
US20050202073A1 (en) * 2004-03-09 2005-09-15 Mylan Technologies, Inc. Transdermal systems containing multilayer adhesive matrices to modify drug delivery
US8343538B2 (en) * 2004-10-08 2013-01-01 Noven Pharmaceuticals, Inc. Compositions and methods for controlling the flux of a drug from a transdermal drug delivery systems

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995008324A1 (fr) * 1993-09-22 1995-03-30 Lts Lohmann Therapie-Systeme Gmbh Pansement contenant des principes actifs volatils susceptible d'etre produit sans solvants

Also Published As

Publication number Publication date
AU2004285505B2 (en) 2010-12-23
IL174894A0 (en) 2006-08-20
AU2004285505A1 (en) 2005-05-12
GEP20084561B (en) 2008-12-10
BRPI0416063A (pt) 2007-01-02
US20140243764A1 (en) 2014-08-28
KR20060114338A (ko) 2006-11-06
WO2005042055A3 (fr) 2005-08-25
UA84303C2 (ru) 2008-10-10
CA2542778C (fr) 2012-05-29
CN100457064C (zh) 2009-02-04
US20100310610A1 (en) 2010-12-09
EP1682061A4 (fr) 2011-12-07
JP2007509951A (ja) 2007-04-19
ES2626784T3 (es) 2017-07-26
JP2013237691A (ja) 2013-11-28
ZA200603300B (en) 2007-07-25
ME00114B (me) 2011-02-10
RU2356580C2 (ru) 2009-05-27
WO2005042055A2 (fr) 2005-05-12
NZ546992A (en) 2009-07-31
CA2542778A1 (fr) 2005-05-12
RS20060332A (en) 2008-04-04
US20050169977A1 (en) 2005-08-04
EP1682061A2 (fr) 2006-07-26
CN1901861A (zh) 2007-01-24
NO20062434L (no) 2006-07-14
RU2006118341A (ru) 2007-12-20
US8703175B2 (en) 2014-04-22
MEP23508A (en) 2010-06-10

Similar Documents

Publication Publication Date Title
EP1682061B1 (fr) Dispositif d'administration de medicaments par voie transdermique
US8865207B2 (en) Compositions and methods for delivering active agents in transdermal drug delivery systems
EP1061900B1 (fr) Compositions et procedes pour l'administration de medicament
US9668981B2 (en) Device for transdermal administration of drugs including acrylic based polymers
US8187628B2 (en) Dermal composition for controlling drug flux comprising two acrylic adhesive polymers having different functionalities and different solubility parameters
US20030152616A1 (en) Crystallization inhibition of drugs in transdermal drug delivery systems and methods of use
WO2001052823A2 (fr) Compositions et methodes permettant d'elaborer un profil de liberation dans l'administration transdermique d'agents actifs
US8586080B1 (en) Inhibiting crystallization of steroidal hormones in transdermal delivery systems
MXPA06004788A (en) Transdermal drug delivery device

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20060524

AK Designated contracting states

Kind code of ref document: A2

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LI LU MC NL PL PT RO SE SI SK TR

AX Request for extension of the european patent

Extension state: AL HR LT LV MK

REG Reference to a national code

Ref country code: HK

Ref legal event code: DE

Ref document number: 1090829

Country of ref document: HK

REG Reference to a national code

Ref country code: DE

Ref legal event code: R079

Ref document number: 602004050927

Country of ref document: DE

Free format text: PREVIOUS MAIN CLASS: A61F0013000000

Ipc: A61K0009700000

A4 Supplementary search report drawn up and despatched

Effective date: 20111109

RIC1 Information provided on ipc code assigned before grant

Ipc: A61K 9/70 20060101AFI20111103BHEP

Ipc: A61F 13/00 20060101ALI20111103BHEP

17Q First examination report despatched

Effective date: 20120430

REG Reference to a national code

Ref country code: HK

Ref legal event code: WD

Ref document number: 1090829

Country of ref document: HK

GRAP Despatch of communication of intention to grant a patent

Free format text: ORIGINAL CODE: EPIDOSNIGR1

INTG Intention to grant announced

Effective date: 20160901

GRAS Grant fee paid

Free format text: ORIGINAL CODE: EPIDOSNIGR3

GRAA (expected) grant

Free format text: ORIGINAL CODE: 0009210

RIN1 Information on inventor provided before grant (corrected)

Inventor name: KANIOS, DAVID P.

Inventor name: HOUZE, DAVID W.

Inventor name: HARTWIG, ROD

Inventor name: MANTELLE, JUAN A.

AK Designated contracting states

Kind code of ref document: B1

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LI LU MC NL PL PT RO SE SI SK TR

AX Request for extension of the european patent

Extension state: AL HR LT LV MK

REG Reference to a national code

Ref country code: CH

Ref legal event code: EP

Ref country code: GB

Ref legal event code: FG4D

REG Reference to a national code

Ref country code: IE

Ref legal event code: FG4D

REG Reference to a national code

Ref country code: AT

Ref legal event code: REF

Ref document number: 874841

Country of ref document: AT

Kind code of ref document: T

Effective date: 20170415

REG Reference to a national code

Ref country code: DE

Ref legal event code: R096

Ref document number: 602004050927

Country of ref document: DE

REG Reference to a national code

Ref country code: NL

Ref legal event code: MP

Effective date: 20170315

REG Reference to a national code

Ref country code: ES

Ref legal event code: FG2A

Ref document number: 2626784

Country of ref document: ES

Kind code of ref document: T3

Effective date: 20170726

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: GR

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20170616

Ref country code: FI

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20170315

REG Reference to a national code

Ref country code: AT

Ref legal event code: MK05

Ref document number: 874841

Country of ref document: AT

Kind code of ref document: T

Effective date: 20170315

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: SE

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20170315

Ref country code: BG

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20170615

REG Reference to a national code

Ref country code: FR

Ref legal event code: PLFP

Year of fee payment: 14

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: NL

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20170315

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: EE

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20170315

Ref country code: RO

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20170315

Ref country code: CZ

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20170315

Ref country code: SK

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20170315

Ref country code: AT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20170315

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: PL

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20170315

Ref country code: PT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20170717

REG Reference to a national code

Ref country code: DE

Ref legal event code: R097

Ref document number: 602004050927

Country of ref document: DE

PLBE No opposition filed within time limit

Free format text: ORIGINAL CODE: 0009261

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: NO OPPOSITION FILED WITHIN TIME LIMIT

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: DK

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20170315

26N No opposition filed

Effective date: 20171218

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: SI

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20170315

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: MC

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20170315

REG Reference to a national code

Ref country code: CH

Ref legal event code: PL

REG Reference to a national code

Ref country code: IE

Ref legal event code: MM4A

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: LU

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20171028

Ref country code: CH

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20171031

Ref country code: LI

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20171031

REG Reference to a national code

Ref country code: BE

Ref legal event code: MM

Effective date: 20171031

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: BE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20171031

REG Reference to a national code

Ref country code: FR

Ref legal event code: PLFP

Year of fee payment: 15

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: IE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20171028

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: HU

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT; INVALID AB INITIO

Effective date: 20041028

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: CY

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20170315

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: FR

Payment date: 20190924

Year of fee payment: 16

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: GB

Payment date: 20190925

Year of fee payment: 16

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: DE

Payment date: 20190917

Year of fee payment: 16

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: IT

Payment date: 20191022

Year of fee payment: 16

Ref country code: ES

Payment date: 20191104

Year of fee payment: 16

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: TR

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20170315

REG Reference to a national code

Ref country code: DE

Ref legal event code: R119

Ref document number: 602004050927

Country of ref document: DE

GBPC Gb: european patent ceased through non-payment of renewal fee

Effective date: 20201028

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: DE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20210501

Ref country code: FR

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20201031

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: GB

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20201028

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: IT

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20201028

REG Reference to a national code

Ref country code: ES

Ref legal event code: FD2A

Effective date: 20220128

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: ES

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20201029